WNT, stem cell functions and acute myeloid leucemia

Coordinator:    Prof. Dr. Achim Leutz
Institution: Max-Delbrück-Zentrum für molekulare Medizin, Berlin
A small population of self-renewing tumor stem cells maintain the malignant phenotype in many hematological tumors. Tumor initiating cells activate genes that normally regulate self-renewal of embryonic and adult stem cells. The tumor stem cells have, however, lost the ability to communicate properly with other cells, to differentiate into functional cells, and instead generate dysfunctional, malignant tumor cells. It is therefore important to identify the pathways, their interconnections and molecular mechanisms that control normal and malignant stem cell functions. This will improve our understanding, how genetic programs are subverted during tumor formation.

Canonical WNT-signaling through beta-catenin is a highly conserved onco-developmental pathway implicated in self-renewal of stem cells in many different tissues, including the hematopoietic system. Deregulation of canonical Wnt signaling is linked to initiation and progression of various cancers. A recent study in patients with chronic myeloid leukemia (CML) blast crisis identified a population of Bcr-Abl-positive granulocyte macrophage progenitors that express nuclear beta-catenin and that have acquired self-renewal capacity (Jamison et al., 2004). Using mouse genetics, we have recently shown that constitutive activation of the canonical WNT-pathway by genetic stabilization of beta-catenin led to expansion of hematopoietic stem cells (Scheller et al., 2006). Further analysis demonstrated that activated beta-catenin blocked differentiation in all hematopoietic lineages and suggested that fine-tuning of WNT-stimulation is essential for normal hematopoiesis. Interestingly, activation of conditional beta-catenin /WNT signaling in mice led to expansion of the stem cell compartment and to a phenotype that in many respects resembled early onset of acute myeloid leukemia (AML) in human. However, full progression to leukemia was not observed in the mouse, suggesting that additionally mutations are required to generate beta-catenin induced cancer stem cells. We have therefore started to combine a conditionally activated beta-catenin with other genetic lesions that are frequently found in human leukemia to recapitulate the steps of human leukemogenesis. Such a mouse model will permit to examine the mechanisms involved in generation of tumor stem cells and advancement of the disease.

Expansion von Blastenzellen im Knochenmark nach Aktivierung von beta-catenin
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